1. Field of the Invention
The present invention involves improved processes for the dehalogenation of a 9.alpha.-halosteroids (I) to produce the corresponding 11.beta.-hydroxy steroids (II) which are known to be useful as pharmaceuticals.
2. Description of the Related Art
11.beta.-Hydroxy steroids, especially corticoids, are very important commercial steroids. These can generally be made two ways; first by fermentation with a microorganism which will hydroxylate at the 11 position in the .beta. configuration and second by starting with a .increment..sup.9(11) -steroid, forming the halohydrin and then dehalogenating. Processes for dehalogenation of 9.alpha.-halo-11.beta.-hydroxy steroids are known.
U.S. Pat. No. 3,480,622 discloses a process for the debromination of a 9.alpha.-bromo-11.beta.-hydroxy steroid by reaction of the brominated steroid with a salt of a polyvalent metal (chromium) in which the metal is transformed from a lower oxidation state (+2) to a higher state (+3) in the presence of a compound capable of providing hydrogen radicals preferably a thiol. U.S. Pat. No. 3,480,622 discloses that the metal reducing agent, preferably chromous acetate, is ". . . present in at least stoichiometric quantities with respect to the steroid and is advantageously in excess. 1 to 10 moles of reducing agent may, for example, be used, preferably about 5 mole." Further, that "The reaction temperature does not appear to be critical . . . " -50.degree. to 100.degree. being operable and 20.degree.-25.degree. is convenient. While no order of addition of reactants is taught, in the specification, in all the examples the metal reducing agent, chromous acetate, was added to the 9.alpha. -bromo steroid. This patent states the claimed process gives yields of 75-80%. U.S. Pat. No. 3,480,622 discloses four examples. Two examples are to 11.beta.-fluoro steroids. The two other examples, examples 10 and 14(b), involve 11.beta.-hydroxy functionality in the C-ring, having .increment..sup.1,4 -3-keto functionality in the steroid A-ring and gave yields of 70 and 80% respectively. US patent did not recycle the chromium (III) produced by the dehalogenation to chromium (II), hence at least one equivalent of chromium (II) was required. Preferred was 5 equivalents.
U.S. Pat. Nos. 4,304,727 and 4,325,881 improved upon the process of U.S. Pat. No. 3,480,622 by using thioglycolic acid as the thiol (hydrogen radical source). These two patents teach (with the exception of Example 7 in both patents) that the chromous ion should be present in "A slight excess over theory . . . . " These two patents also state "Temperature is not critical, -50.degree. to 100.degree. being suitable, 20.degree.-50.degree. being preferred." These two patents like U.S. Pat. No. 3,480,622 also do not mention the order of addition of reactants in the non-example portion of the specification. However, like U.S. Pat. No. 3,480,622, in the EXAMPLES these patents disclose only the addition of the chromous ion to the 9.alpha.-bromo steroid. The process in these patents did not recycle the chromium (III) produced by the dehalogenation to chromium (II), hence the requirement that a slight excess over theory, at least one equivalent of chromium (II), be used. Example 7 of U.S. Pat. Nos. 4,304,727 and 4,325,881 used 0.21 equivalents of chromium and reported a chemical yield of 83%. It has been found that the yield obtained in Example 7 of U.S. Pat. Nos. 4,304,727 and 4,325,881 was due to the zinc present and not the chromium which was not soluble under those conditions, compare EXAMPLES 6 and 7 in CHART B.
Tetrahedron Letters 43, 3151 (1964) [BARTON I] discloses that 9.alpha.-bromoprogesterone can be debrominated using 5 equivalents of chromous acetate at room temperature in 6-13 hr in 80% yield. Similarly, the .increment..sup.1,4 -steroid, 9.alpha.-bromoprednisolone 21-acetate was debrominated in 74% yield.
J. Am. Chem. Soc., 88, 3016 (1966) [BARTON II] and J. Org. Chem., 31, 2749 (1966) [BARTON III] propose mechanistic interpretations of the results of BARTON I and additional studies of chromous ion reductions.
The processes of the present invention dehalogenate 9.alpha.-halo steroids in &gt;90% conversion by (1) adding the steroid to the chromium ion rather than adding the chromium ion to the steroid and (2) using &lt;1 equivalent of soluble chromium ion in the presence of a means for converting chromium (III) to chromium (II).